CLORAZEPATE DIPOTASSIUM
Clinical safety rating: avoid
Positive evidence of fetus risks but benefits may outweigh risks in some cases
Binds to benzodiazepine site on gamma-aminobutyric acid type A (GABAA) receptors, enhancing GABA-mediated chloride ion influx, leading to neuronal hyperpolarization and decreased excitability.
| Metabolism | Hepatic; primarily metabolized by CYP3A4 and CYP2C19 to active metabolite N-desmethyldiazepam (nordazepam); other active metabolites include oxazepam and temazepam. |
| Excretion | Primarily renal (60-70% as oxazepam glucuronide and other metabolites), with 15-20% biliary/fecal elimination. Less than 1% excreted unchanged. |
| Half-life | 40-50 hours (clorazepate is a prodrug rapidly converted to nordiazepam); effective half-life of nordiazepam is 40-100 hours. Accumulation occurs with repeated dosing, leading to prolonged sedation in elderly or hepatic impairment. |
| Protein binding | 85-95% bound, primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | 0.15-0.3 L/kg for clorazepate; nordiazepam Vd is 0.5-1.0 L/kg. Clinical meaning: moderate distribution, with higher Vd in obesity due to lipophilicity. |
| Bioavailability | Oral: ~100% (rapidly hydrolyzed to nordiazepam in GI tract); intravenous: not available. IM: not recommended due to erratic absorption. |
| Onset of Action | Oral: 30-60 minutes; peak effects at 1-2 hours. Rapid conversion to nordiazepam (t1/2 of conversion ~2 hours) allows for anxiolytic effect within 1 hour. |
| Duration of Action | Anxiolytic: 24-36 hours; anticonvulsant: 12-24 hours. Long duration due to active metabolite nordiazepam; steady-state achieved in 5-7 days. |
15-60 mg/day orally in divided doses 2-4 times daily; usual starting dose 15 mg at bedtime or 15 mg twice daily.
| Dosage form | CAPSULE |
| Renal impairment | GFR 10-50 mL/min: administer 50% of usual dose; GFR <10 mL/min: administer 25% of usual dose or not recommended. |
| Liver impairment | Child-Pugh Class A: consider 50% dose reduction; Child-Pugh Class B or C: contraindicated or use with extreme caution, maximum 15 mg/day. |
| Pediatric use | Not recommended for patients under 9 years; for ages 9-12: 7.5 mg twice daily initially, max 60 mg/day; for ages 12-18: same as adult dosing. |
| Geriatric use | Initial dose 7.5 mg/day orally, may increase to 15 mg/day; avoid doses >30 mg/day; monitor for excessive sedation and falls. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CNS depressants including alcohol and opioids increase sedation risk Abrupt discontinuation can cause withdrawal symptoms.
| Breastfeeding | Excreted into breast milk; M/P ratio not established. Limited data suggest infant doses <10% of maternal weight-adjusted dose. Monitor infant for sedation, poor feeding, and weight gain. Use caution; discontinue breastfeeding if infant shows adverse effects. Manufacturers recommend avoiding due to potential accumulation. |
| Teratogenic Risk | First trimester: Increased risk of oral clefts (odds ratio ~2.2) based on animal and limited human data. Second and third trimesters: Risk of neonatal withdrawal syndrome (irritability, hypertonia, feeding difficulties) and floppy infant syndrome (hypotonia, lethargy, poor suck) following chronic exposure. Use only if benefit clearly outweighs risk. |
■ FDA Black Box Warning
Coadministration with opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for patients without alternative treatment options.
| Common Effects | Sedation |
| Serious Effects |
["Hypersensitivity to clorazepate or any benzodiazepine","Acute narrow-angle glaucoma","Severe hepatic impairment","Pregnancy (especially first trimester)","Nursing mothers"]
| Precautions | ["Severe anaphylactic reactions","Central nervous system depression (concomitant CNS depressants)","Physical and psychological dependence (avoid abrupt discontinuation)","Acute withdrawal (including seizures) with dose reduction","Epilepsy (taper abruptly may exacerbate seizures)","Paradoxical reactions (hyperactivity, aggression)","Renal impairment (dose adjustment may be required)","Hepatic impairment (dose reduction recommended)","Use in pregnancy (risk of congenital malformations; neonatal withdrawal/SSR)"] |
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| Fetal Monitoring | Monitor maternal for excessive sedation, dependence, withdrawal symptoms. Fetal: Ultrasound for growth abnormalities if chronic use. Neonatal: Observe for withdrawal symptoms (hypertonia, tremors, irritability) for 48-72 hours postpartum; floppy infant syndrome may persist for weeks. |
| Fertility Effects | Animal studies show no impairment of fertility at clinically relevant doses. Human data insufficient; theoretical risk of hormonal disruption with chronic high-dose use. No well-controlled studies on human fertility. |